Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial.
BACKGROUND
Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Our aim was to show non-inferiority of a new dispersible formulation of artemether-lumefantrine to the conventional crushed tablet in the treatment of young children with uncomplicated malaria.


METHODS
We did a randomised non-inferiority study on children weighing 5-35 kg with uncomplicated P falciparum malaria in Benin, Kenya, Mali, Mozambique, and Tanzania. The primary outcome measure was PCR-corrected 28-day parasitological cure rate. We aimed to show non-inferiority (with a margin of -5%) of dispersible versus crushed tablet. We constructed an asymptotic one-sided 97.5% CI on the difference in cure rates. A computer-generated randomisation list was kept centrally and investigators were unaware of the study medication administered. We used a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00386763.


RESULTS
899 children aged 12 years or younger were randomly assigned to either dispersible (n=447) or crushed tablets (n=452). More than 85% of patients in each treatment group completed the study. 812 children qualified for the modified intention-to-treat analysis (n=403 vs n=409). The PCR-corrected day-28 cure rate was 97.8% (95% CI 96.3-99.2) in the group on dispersible formulation and 98.5% (97.4-99.7) in the group on crushed formulation. The lower bound of the one-sided 97.5% CI was -2.7%. The most common drug-related adverse event was vomiting (n=33 [7%] and n=42 [9%], respectively). No signs of ototoxicity or relevant cardiotoxicity were seen.


CONCLUSIONS
A six-dose regimen of artemether-lumefantrine with the new dispersible formulation is as efficacious as the currently used crushed tablet in infants and children, and has a similar safety profile.
Abdulla
Salim
S
Ifakara Health Institute, Dar es Salaam, Tanzania.
Sagara
Issaka
I
Borrmann
Steffen
S
D'Alessandro
Umberto
U
González
Raquel
R
Hamel
Mary
M
Ogutu
Bernhards
B
Mårtensson
Andreas
A
Lyimo
John
J
Maiga
Hamma
H
Sasi
Philip
P
Nahum
Alain
A
Bassat
Quique
Q
Juma
Elizabeth
E
Otieno
Lucas
L
Björkman
Anders
A
Beck
Hans Peter
HP
Andriano
Kim
K
Cousin
Marc
M
Lefèvre
Gilbert
G
Ubben
David
D
Premji
Zulfikarali
Z
D017954:Africa South of the Sahara; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D013607:Tablets; D016896:Treatment Outcome
D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D013607:Tablets